Mitochondrial Protein TAMM41 Modulates Depressive-like Behaviors.

Several lines of evidence have highlighted the crucial role of mitochondria-based therapy in depression. However, there are still less mitochondrial targets for the depression treatment. TAM41 mitochondrial translocator assembly and maintenance homolog (TAMM41) is a mitochondrial inner membrane protein for maintaining mitochondrial function, which is tightly related to many brain diseases including Alzheimer's diseases and epilepsy. Here, we investigated whether TAMM41 would be a potential target to treat depression. We found that the expression of TAMM41 was markedly lower in corticosterone-induced depression, lipopolysaccharide-induced depression, and depressed patients. Meanwhile, loss of TAMM41 resulted in increased immobility in the forced swim test (FST), tail suspension test (TST), and center time in open field test (OFT), suggesting depressive-like behaviors in mice. Moreover, genetic overexpression of TAMM41 obviously exerted antidepressant-like activities. Mechanistically, proteomics revealed that pacsin1 might be the underlying target of TAMM41. Further data supported that TAMM41 regulated the expression of pacsin1, and its antidepressant-like effect at least partially was attributed to pacsin1. In addition, exosomes containing TAMM41 was sufficient to exhibit antidepressant-like effect, suggesting an alternative strategy to exert the effect of TAMM41. Taken together, the present study demonstrates the antidepressant-like effect of TAMM41 and sheds light on its molecular mechanism. These finding provide new insights into a therapeutic strategy targeting mitochondria in the development of novel antidepressants.

Effects of silencing hsa_circ_0015326 on proliferation, migration, invasion, and apoptosis of epithelial ovarian cancer cells.

Although the treatment of ovarian cancer has made great progress, there are still many patients who are not timely detected and given targeted therapy due to unknown pathogenesis. Recent studies have found that hsa_circ_0015326 is upregulated in ovarian cancer and is involved in the proliferation, invasion, and migration of ovarian cancer cells. However, whether hsa_circ_0015326 can be used as a new target of ovarian cancer needs further investigation. Therefore, the effect of hsa_circ_0015326 on epithelial ovarian cancer was investigated in this study. At first, si-hsa_circ_0015326 lentivirus was transfected into epithelial ovarian cancer cells. Then real-time fluorescence quantitative PCR (qRT-PCR) was used to detect hsa_circ_0015326 level. The proliferation of ovarian cancer cells was detected by CCK-8 assay. The horizontal and vertical migration abilities of the cells were detected by wound-healing assay and Transwell assay, respectively. Transwell assay was also used to determine the invasion rate. As for the apoptosis rate, it was assessed by flow cytometry. As a result, the expression level of hsa_circ_0015326 in A2780 and SKOV3 was found to be higher than that in IOSE-80. However, after transfecting si-hsa_circ_0015326 and si-NC into the cells, the proliferation, migration, and invasion abilities of A2780 and SKOV3 cells in the si-hsa_circ_0015326 group were significantly reduced in comparison to those in the si-NC and mock groups, while their apoptosis rates were elevated. Collectively, silencing hsa_circ_0015326 bears the capability of inhibiting the proliferation, migration, and invasion of ovarian cancer cells while increasing apoptosis rate. It can be concluded that hsa_circ_0015326 promotes the malignant biological activities of epithelial ovarian cancer cells.

Sociodemographic, clinical and treatment characteristics of current rapid-cycling bipolar disorder: a multicenter Chinese study.

BACKGROUND: Rapid cycling bipolar disorder (RCBD), characterized by four or more episodes per year, is a complex subtype of bipolar disorder (BD) with poorly understood characteristics. METHOD: This multicenter, observational, longitudinal cohort study enrolled 520 BD patients across seven psychiatric institutions in China from January 2013 to January 2014. Participants were divided into RCBD and non-RCBD (NRCBD) groups based on the frequency of mood episodes in the preceding year. Data collection utilized a standardized form, supplemented by a medical record review, focusing on sociodemographic, clinical, and treatment characteristics. Statistical analysis involved independent samples t-tests, Kruskal-Wallis H tests, Chi-square or Fisher's exact tests, with Bonferroni correction applied to account for multiple comparisons, and multivariable logistic regression to identify characteristics associated with RCBD. RESULTS: Among the BD cohort, 9.4% were identified as current RCBD. Compared to NRCBD, RCBD patients had a shorter duration from the first psychiatric consultation to the diagnosis of BD, a reduced duration of their longest period of euthymia, a lower proportion of lifetime hospitalization history due to BD, and less use of electroconvulsive therapy (ECT) within the last 12 months. Additionally, they presented higher baseline scores on the Mood Disorder Questionnaire (MDQ) and the Brief 16-item Quick Inventory of Depressive Symptomatology Self-Report (QIDS-SR16). However, after applying the Bonferroni correction, these differences were not statistically significant. Multivariable logistic regression analysis identified three factors that were independently associated with RCBD: time from first psychiatric consultation to BD diagnosis (Odds Ratio [OR] = 0.512, P = 0.0416), lifetime hospitalization history due to BD (OR = 0.516, P = 0.0476), and ECT treatment within the past 12 months (OR = 0.293, P = 0.0472). CONCLUSION: This study revealed that the duration from first psychiatric consultation to BD diagnosis, lifetime hospitalization history due to BD, and ECT treatment in the past year were associated with RCBD. Recognizing these factors could contribute to enhance the early identification and clinical outcomes of RCBD. Trial Registration Number Registry ClinicalTrials.gov NCT01770704. Date of Registration: First posted on January 18, 2013.

Potato calcium sensor modules StCBL3-StCIPK7 and StCBL3-StCIPK24 negatively regulate plant immunity.

BACKGROUND: Potato late blight, caused by Phytophthora infestans, is the most devastating disease on potato. Dissecting critical immune components in potato will be supportive for engineering P. infestans resistance. Upon pathogens attack, plant Ca2+ signature is generated and decoded by an array of Ca2+ sensors, among which calcineurin B-like proteins (CBLs) coupled with plant specific CBL-interacting protein kinases (CIPKs) are much less explored in plant immunity. RESULTS: In this study, we identified that two differential potato CBL-CIPK modules regulate plant defense responses against Phytophthora and ROS production, respectively. By deploying virus-induced gene silencing (VIGS) system-based pathogen inoculation assays, StCBL3 was shown to negatively regulate Phytophthora resistance. Consistently, StCBL3 was further found to negatively regulate PTI and ETI responses in Nicotiana benthamiana. Furthermore, StCIPK7 was identified to act together with StCBL3 to negatively regulate Phytophthora resistance. StCIPK7 physically interacts with StCBL3 and phosphorylates StCBL3 in a Ca2+-dependent manner. StCBL3 promotes StCIPK7 kinase activity. On the other hand, another StCBL3-interacting kinase StCIPK24 negatively modulating flg22-triggered accumulation of reactive oxygen species (ROS) by interacting with StRBOHB. CONCLUSIONS: Together, these findings demonstrate that the StCBL3-StCIPK7 complex negatively modulates Phytophthora resistance and StCBL3-StCIPK24 complex negatively regulate ROS production. Our results offer new insights into the roles of potato CBL-CIPK in plant immunity and provide valuable gene resources to engineer the disease resistance potato in the future.

Association of residential greenness, air pollution with adverse birth outcomes: Results from 61,762 mother­neonatal pairs in project ELEFANT (2011-2021).

BACKGROUND: Emerging evidence has demonstrated the benefits of greenness exposure on human health, while conflicts remain unsolved in issue of adverse birth outcomes. METHODS: Utilizing data from project ELEFANT spanning the years 2011 to 2021, we assessed residential greenness using the NDVI from MODIS data and residential PM2.5 exposure level from CHAP data. Our primary concerns were PTD, LBW, LGA, and SGA. Cox proportional hazard regression model was used to examine the association of residential greenness and air pollution exposure with risk of adverse birth outcomes. We performed mediation and modification effect analyses between greenness and air pollutant. RESULTS: We identified 61,762 mother­neonatal pairs in final analysis. For per 10 µg/m3 increase in PM2.5 concentration during entire pregnancy was associated with 19.8 % and 20.7 % increased risk of PTD and LGA. In contrast, we identified that an 0.1 unit increment in NDVI were associated with 24 %, 43 %, 26.5 %, and 39.5 % lower risk for PTD, LBW, LGA, and SGA, respectively. According to mediation analysis, NDVI mediated 7.70 % and 7.89 % of the associations between PM2.5 and PTD and LGA. Residential greenness could reduce the risk of PTD among mothers under 35 years old, living in rural areas, primigravidae and primiparity.. CONCLUSIONS: In summary, our results highlighted the potential of residential greenness to mitigate the risk of adverse birth outcomes, while also pointing to the adverse impact of PM2.5 on increased risk of multiple adverse birth outcomes (PTD and LGA). The significant mediation effect of NDVI emphasizes its potential as an important protective factor of PM2.5 exposure. Additionally, the identification of susceptible subgroups can inform targeted interventions to reduce adverse birth outcomes related to air pollution and lack of green spaces. Further research and understanding of these associations can contribute to better public health strategies aimed at promoting healthier pregnancies and birth outcomes.

SARS-CoV-2 spike receptor-binding domain is internalized and promotes protein ISGylation in human induced pluripotent stem cell-derived cardiomyocytes.

Although an increased risk of myocarditis has been observed after vaccination with mRNA encoding severe acute respiratory syndrome coronavirus 2 spike protein, its underlying mechanism has not been elucidated. This study investigated the direct effects of spike receptor-binding domain (S-RBD) on human cardiomyocytes differentiated from induced pluripotent stem cells (iPSC-CMs). Immunostaining experiments using ACE2 wild-type (WT) and knockout (KO) iPSC-CMs treated with purified S-RBD demonstrated that S-RBD was bound to ACE2 and internalized into the subcellular space in the iPSC-CMs, depending on ACE2. Immunostaining combined with live cell imaging using a recombinant S-RBD fused to the superfolder GFP (S-RBD-sfGFP) demonstrated that S-RBD was bound to the cell membrane, co-localized with RAB5A, and then delivered from the endosomes to the lysosomes in iPSC-CMs. Quantitative PCR array analysis followed by single cell RNA sequence analysis clarified that S-RBD-sfGFP treatment significantly upregulated the NF-kß pathway-related gene (CXCL1) in the differentiated non-cardiomyocytes, while upregulated interferon (IFN)-responsive genes (IFI6, ISG15, and IFITM3) in the matured cardiomyocytes. S-RBD-sfGFP treatment promoted protein ISGylation, an ISG15-mediated post-translational modification in ACE2-WT-iPSC-CMs, which was suppressed in ACE2-KO-iPSC-CMs. Our experimental study demonstrates that S-RBD is internalized through the endolysosomal pathway, which upregulates IFN-responsive genes and promotes ISGylation in the iPSC-CMs.

The effect of gender on the clinical outcome of PD-1/PD-L1 inhibitor in advanced lung cancer patients.

BACKGROUND: Programmed death protein-1/ligand-1 (PD-1/L1) inhibitors have widely used in the treatment of lung cancer. Some literatures indicated that different gender might not have equal immune response, but no agreement have reached on the issue. Hence, we performed a systematic review and meta-analysis that examine the effect of gender on the clinical outcome of PD-1/PD-L1 inhibitor in advanced lung cancer patients. METHODS: Related database and conferences were searched. Studies that reported the relationship between gender and the overall survival (OS) or progression-free survival (PFS) of PD-1/L1 inhibitor were included. Meta-analysis was conducted to obtain pooled hazard ratios (HRs) with 95% CI. RESULTS: We included 34 studies with 11,883 lung cancer patients. Meta-analysis showed that PD-1/PD-L1 inhibitors significantly prolonged the OS (males: HR 0.71, 95%CI 0.66-0.77; females: HR 0.72, 95%CI 0.63-0.82) and PFS (males: HR 0.60, 95%CI 0.55-0.66; females: HR 0.72, 95%CI 0.62-0.84) versus chemotherapy. The clinical benefit (OS HR: 0.99; PFS HR: 0.83) was not statistically significant between males and females. In patients treated with cemiplimab, male patients had a better OS (0.53, 95%CI 0.42-0.66) and PFS (OS 1.51, 95%CI 0.80-2.82) compared with female patients, but the small number of female patients precludes us from drawing any firm conclusions in female subpopulations. CONCLUSION: The clinical benefit of PD-1/PD-L1 inhibitors was not statistically significant between males and females during the treatment of lung cancer. In the future, researchers who are designing new immunotherapy studies should ensure a larger inclusion of women in trials, to avoid erroneously extending to women results that are obtained mainly in male patients.

Immune-inflammatory responses and pulmonary embolism in Catatonia: A report of two cases.

Venous thromboembolism (VTE) comprises pulmonary embolism (PE) and deep vein thrombosis (DVT). PE, as the most severe manifestation of VTE, can cause increased mortality in patients with mental disorders. Here we describe two cases of young male patients with catatonia who developed PE and DVT during their hospital stay. We also discuss the possible pathogenesis, with a focus on immune and inflammatory mechanisms.

The inhibitory effect of KIAA1456 on the proliferation and metastasis of epithelial ovarian cancer through SSX1 and AKT signaling pathway.

Background: KIAA1456 is effective in the inhibition of tumorigenesis. We previously confirmed that KIAA1456 inhibits cell proliferation and metastasis in epithelial ovarian cancer (EOC). In the current study, the specific molecular mechanisms and clinical significance of KIAA1456 underlying the repression of EOC were investigated. Methods: Immunohistochemistry was used to evaluate the protein expression of KIAA1456 and SSX1 in EOC and normal ovarian tissues. The relationship of KIAA1456 and SSX1 with overall survival of patients with EOC was analysed with Kaplan-Meier survival curve and log-rank tests. KIAA1456 was overexpressed and silenced in HO8910PM cells with lentivirus. Anticancer activities of KIAA1456 was tested by CCK8, plate clone formation assay, flow cytometry, wound healing assay and Transwell invasion assay. Xenograft tumour models were used to investigate the effects of KIAA1456 on tumour growth in vivo. Bioinformatics analyses of microarray profiling indicated that SSX1 and the PI3K/AKT were differentially expressed in KIAA1456-overexpressing and control cells. The downstream factors of PI3K/AKT that are related to cell growth and apoptosis. Results: KIAA1456 expression was lower in EOC than in normal ovarian tissues. Its expression negatively correlated with pathological grade. Pearson's correlation analysis showed that KIAA1456 negatively correlated with SSX1 expression. The overexpression of KIAA1456 in HO8910PM cells inhibited proliferation, migration and invasion and promoted apoptosis. The silencing of KIAA1456 resulted in the opposite behaviour. A xenograft tumour experiment showed that KIAA1456 overexpression inhibited tumour growth in vivo. The overexpression of KIAA1456 inhibited SSX1 and AKT phosphorylation in HO8910PM cells, causing the inactivation of the AKT pathway and eventually reducing the expression of PCNA, CyclinD1, MMP9 and Bcl2. The silencing of KIAA1456 resulted in the opposite behaviour. SSX1 overexpression could partially reverse the KIAA1456-induced biological effect. Conclusion: KIAA1456 may serve as a tumour suppressor via the inactivation of SSX1 and the AKT pathway, providing a promising therapeutic target for EOC.

GSK-3ß/ß-catenin pathway plays crucial roles in the regulation of NK cell cytotoxicity against myeloma cells.

The plasma cell malignancy, multiple myeloma (MM), has significantly improved by the application of new drugs and autologous hematopoietic stem cell transplantation. However, MM remains incurable. A number of studies have revealed an anti-MM effect of natural killer (NK) cells; however, their clinical efficacy is limited. Furthermore, glycogen synthase kinase (GSK)-3ß inhibitors show an antitumor function. In this study, we aimed to evaluate the potential roles of a GSK-3ß inhibitor (TWS119) in the regulation of NK cell cytotoxicity against MM. Our results showed that, in the presence of TWS119, the NK cell line, NK-92, and in vitro-expanded primary NK cells exhibited a significantly higher degranulation activity, expression of activating receptors, cellular cytotoxicity, and cytokine secretion when they were exposed to MM cells. Mechanistic studies indicated that TWS119 treatment markedly upregulated RAB27A expression, a key molecule for NK cell degranulation, and induced the colocalization of ß-catenin with NF-κB in the nucleus of NK cells. More importantly, GSK-3ß inhibition combined with the adoptive transfer of TWS119-treated NK-92 cells significantly reduced tumor volume and prolonged the survival time of myeloma-bearing mice. In summary, our novel findings suggest that targeting GSK-3ß through the activation of ß-catenin/NF-κB pathway may be an important approach to improve therapeutic efficacy of NK cell transfusion for MM.

Incidence and risk factors for surgical site infection after medial opening-wedge high tibial osteotomy using a locking T-shape plate.

Medial opening-wedge high tibial osteotomy (MOWHTO) is a well-established surgical method for treatment of isolated medial compartment osteoarthritis with varus deformity, but the surgical outcomes may be compromised by surgical site infection (SSI). This study aimed to investigate the incidence and the risk factors for SSI after MOWHTO. This retrospective study included consecutive patients who underwent MOWHTO for isolated medial compartment osteoarthritis with varus deformity in two tertiary referral hospitals from January 2019 and June 2021. Patients who developed SSI within 12 months of surgery were identified by inquiring the medical records for index hospitalisation, notes of after-discharge outpatient visits, or records of readmission for treatment of SSI. Univariate comparisons were performed to detect the differences between SSI and non-SSI groups, and multivariate logistic regression analysis was used to identify the independent risk factors. Six hundred sixteen patients with 708 procedures were included and 30 (4.2%) cases of SSI occurred, with 0.6% rate for deep SSI and 3.6% for superficial. Univariate analyses showed significant difference between groups in terms of morbidity obesity (≥32 kg/m2 ) (20.0% vs 8.9%), comorbid diabetes (26.7% vs 11.1%), active smoking (20.0% vs 6.3%), time from admission to operation (5.2 ± 4.0 vs 4.1 ± 3.0), size of osteotomy ≥12 mm (40.0% vs 20.0%), type of bone grafting and lymphocyte count (2.1 ± 0.5 vs 1.9 ± 0.6). However, in the multivariate analysis, only active smoking (OR, 3.4; 95% CI, 1.4-10.2), size of osteotomy ≥12 mm (OR, 2.8; 95% CI, 1.3-5.9) and allogeneic/artificial vs no bone grafting (OR, 2.4; 95% CI, 1.0-10.8) remained significant. SSI was not uncommon after MOWHTO, but the majority was superficial. The identified three independent factors, including smoking, size of osteotomy ≥12 mm and allogeneic/artificial bone grafting would help risk assessment and stratification, target risk factor modification and clinical surveillance, and inform patient counselling.

Tongluo Shenggu capsule promotes angiogenesis to ameliorate glucocorticoid-induced femoral head necrosis via upregulating VEGF signaling pathway.

BACKGROUND: Tongluo Shenggu Capsule (TLSGC) is a product of Traditional Chinese patent medicine that has been effective in glucocorticoid-induced osteonecrosis of the femoral head (GIONFH) clinically for many years. It is made from water extracts of a well-used herbal and dietary supplement-pigeon pea leaves. Nevertheless, the material basis and pharmacological mechanisms of TLSGC ameliorating GIONFH needed to be better defined. PURPOSE: To investigate the material basis and pharmacological mechanisms of TLSGC to ameliorate GIONFH. METHODS: The chemical compositions in TLSGC were characterized using the LC-MS system. Based on integrating the relevant targets of TLSGC in MedChem Studio software and GIONFH-related genes in our previous work, a "drug targets-disease genes" interaction network was constructed. The candidate targets of TLSGC ameliorating GIONFH were filtrated by topological characteristic parameters and further experimental validated based on methylprednisolone-induced rat model and dexamethasone-inhibited human umbilical vein endothelial cells (HUVECs). RESULTS: A total of 33 chemical compositions were characterized in TLSGC. Based on these compositions and GIONFH-related genes, 122 hub genes were selected according to topological parameters calculation. Biological functions were mainly enriched in four over-expressed modules of vascular damage, inflammation and apoptosis, bone metabolism and energy metabolism. The hub genes had the maximum enrichment degree in the VEGF-VEGFR2-PKC-Raf1-MEK-ERK signaling axis of the VEGF pathway. Experimentally, the therapeutic effects of TLSGC against GIONFH in rats were proved by micro-CT and pathological examination. Then, the protective effects of TLSGC on vascular damage were determined using angiography, CD31 immunohistochemistry, vascular function indicators in vivo, aortic ring test ex vivo, and the HUVECs activities in vitro including migration, invasion and tube formation. Mechanically, TLSGC effectively suppressed the downregulation of VEGF and VEGFR2 and their downstream targets, including Raf-1, PKC, p-MEK, and p-ERK proteins both in vivo and in vitro. CONCLUSION: TLSGC could promote angiogenesis by upregulating the VEGF-VEGFR2-PKC-Raf-1-MEK-ERK signaling axis, thereby exerting an apparent curative effect on GIONFH.

Label-free proteomics analysis on the envelope of budded viruses of Bombyx mori nucleopolyhedrovirus harboring differential localized GP64.

Bombyx mori nucleopolyhedrovirus (BmNPV) GP64 is the key membrane fusion protein that mediates budded virus (BV) infection. We recently reported that BmNPV GP64's n-region of signal peptide (SP) blocked the SP-cleavage and mediated GP64 localization on the plasma membrane (PM); n-region (SP∆nGP64) absence caused GP64 intracellular localization, however, SP∆nGP64 was still incorporated into virion to generate BVs with lower infectivity. To better understand the biogenesis of the envelope of BmNPV BV, we conducted a label-free ESI mass spectrometry analysis of the envelope of purified BVs harboring PM localized GP64 or intracellular localized SP∆nGP64. The results indicated that 31 viral proteins were identified on the envelope, among which 15 were reported in other viruses. The other 16 proteins were first reported in BmNPV BV, including the BmNPV-specific protein BRO-A and proteins associated with vesicle transportation. Six proteins with significant intensity differences were detected in virions with differential localized GP64, and five specific proteins were identified in virions with GP64. Meanwhile, we identified 81 host proteins on the envelope, and seven lipoproteins were first identified in baculovirus virion; other 74 proteins are involved in the cytoskeleton, DNA-binding, vesicle transport, etc. In the meantime, eight and five specific host proteins were, respectively, identified in GP64 and SP∆nGP64's virions. The two virions shared 68 common host proteins, and 8 proteins were identified on their envelopes with a significant difference. This study provides new insight into the protein composition of BmNPV BV and a clue for further investigation of the budding mechanism of BmNPV.

Compartmentalized activities of HMGCS1 control cervical cancer radiosensitivity.

The underlying mechanisms by which cellular metabolism affects cervical cancer cell radiosensitivity remain poorly understood. Here, we found that loss of 3-hydroxy-3-methylglutaryl coenzyme A synthase 1 (HMGCS1), a key enzyme catalyzing the conversion of acetoacetyl-CoA to HMG-CoA in the cholesterol biosynthesis pathway, sensitizes the cervical cancer cells to radiation. We observed a compartmentalized cellular distribution of HMGCS1 in nuclei, cytosol, and mitochondria of cervical cancer cells and found that cytosolic HMGCS1 and mitochondrial HMGCS1 contribute together to the regulation of radiosensitivity. Mechanistically, we show that cytosolic HMGCS1 regulates radiosensitivity via manipulating the cholesterol metabolism, while mitochondrial HMGCS1 controls mitochondrial gene expression, thereby sustaining the mitochondrial function of cervical cancer cells. Together, our study identifies HMGCS1 as a novel regulator of radiosensitivty in cervical cancer cells, providing a molecular link between altered cholesterol metabolism, mitochondrial respiration, and radiosensitivity. Thus, targeting HMGCS1 may improve the therapeutic outcome of cervical cancer radiotherapy.

Human amniotic mesenchymal stem cells promote endometrium regeneration in a rat model of intrauterine adhesion.

Human amniotic transplantation has been proposed to improve the therapeutic efficacy of intrauterine adhesions (IUAs). Human amniotic mesenchymal stem stromal cells (hAMSCs) can differentiate into multiple tissue types. This study aimed to investigate the mechanism by which hAMSCs transplantation promotes endometrial regeneration. The rat models with IUA were established through mechanical and infective methods, and PKH26-labeled hAMSCs were transplanted through the tail vein (combined with/without estrogen). Under three different conditions, hAMSCs differentiated into endometrium-like cells. HE and Mason staining assays, and immunohistochemistry were used to compare the changes in rat models treated with hAMSCs and/or estrogen transplantation. To define the induction of hAMSCs to endometrium-like cells in vitro, an induction medium (cytokines, estrogen) was used to investigate the differentiation of hAMSCs into endometrium-like cells. qRT-polymerase chain reaction (PCR) and western blotting were performed to detect the differentiation of hAMSCs into endometrium-like cells. A greater number of glands, fewer endometrial fibrotic areas, and stronger expression of vascular endothelial growth factor and cytokeratin in the combined group (hAMSCs transplantation combined with estrogen) than in the other treatment groups were observed. hAMSCs could be induced into endometrium-like cells by cytokine treatment (TGF-ß1, EGF, and PDGF-BB). Transplantation of hAMSCs is an effective alternative for endometrial regeneration after injury in rats. The differentiation protocol for hAMSCs will be useful for further studies on human endometrial regeneration.

Case Report: Hypereosinophilic syndrome vs. patent foramen ovale as etiopathogenetic contributors to stroke.

Hypereosinophilic syndrome (HES), characterized by an increased number of eosinophils in tissues and/or blood, presents with heterogeneous clinical manifestations. Studies have shown that HES can affect the nervous system and may be associated with cerebral infarction. Patent foramen ovale (PFO) is the most common congenital intracardiac defect that can cause right-to-left shunting and contribute to the paradoxical embolization of venous emboli, and even lead to stroke. We report the case of a young man who presented with cerebral infarction accompanied by both HES and PFO. The patient underwent thorough evaluation to determine the source of emboli and the potential pathogenesis. In this case, HES was confirmed and glucocorticoid treatment was conducted. Direct imaging using optical coherence tomography (OCT) confirmed that the embolus originated from the PFO. Therefore, we performed PFO occlusion. The patient recovered well, and no new cerebral infarction was observed at 6-month follow-up. Based on the results of our study, we conclude that it is important to consider unusual etiologies of cerebral infarction, particularly in younger patients.

Diverse Galactooligosaccharides Differentially Reduce LPS-Induced Inflammation in Macrophages.

The effects of natural and synthetic galactooligosaccharides (GOS) on inflammation were explored by investigating the structure-activity relationship between the degree of GOS polymerization and in vitro anti-inflammatory activity, together with the potential underlying mechanism of their anti-inflammatory effects. The results demonstrated that GOS had strong anti-inflammatory effects in lipopolysaccharide (LPS)-induced RAW264.7 macrophages, including the inhibition of nitric oxide production and the reduced expression of pro-inflammatory mediators (interleukin-1ß, interleukin-6, and tumor necrosis factor α), induced nitric oxide synthase (iNOS), cyclooxygenase 2 (COX-2), and proteins related to the Toll-like receptor 4 (TLR4)/nuclear factor (NF)-κB signaling pathway. GOS4, which has the highest degree of polymerization, exerted the strongest anti-inflammatory activity among the GOS examined. More importantly, our findings confirmed the anti-inflammatory effects of GOS on RAW264.7 macrophages via the TLR4/NF-κB pathway. Our experimental results could provide further support for the exploration of GOS in human nutrition and health.

Subunit C of V-ATPase-VmaC Is Required for Hyphal Growth and Conidiation in A. fumigatus by Affecting Vacuolar Calcium Homeostasis and Cell Wall Integration.

Aspergillus fumigatus is a widespread airborne fungal pathogen in humans. However, the functional genes in A. fumigatus that may contribute to its pathogenesis have not yet been fully identified. Vacuolar H+-ATPase is universal in eukaryotic organisms but exhibits specific roles in various species. Here, we identified VmaC as a putative subunit of vacuolar H+-ATPase in A. fumigatus that is widely conserved through evolution. The C-terminal hydrophobic domain of VmaC plays a critical role in its vacuolar localization and growth and conidiation. Deletion or turn-off of VmaC encoding gene-AfvmaC expression is not lethal but leads to a very sick and tiny colony phenotype, which is different from that of yeast with conditional ScvmaC defects. Furthermore, we found that AfvmaC not only participates in maintaining calcium homeostasis and vacuolar acidity but is also involved in cell wall integration pathway regulation, highlighting the importance of the vacuole as a storage organelle associated with many aspects of cellular homeostasis. This study indicates that fungal VmaC is relatively conserved. When compared to that in model yeasts, VmaC in A. fumigatus is required for hyphal growth and conidiation, suggesting that specific motifs in VmaC might be functioned in Aspergilli.

Effect of proton pump inhibitors on the clinical outcomes of PD-1/PD-L1 inhibitor in solid cancer patients.

BACKGROUND: Some concomitant drugs may affect the efficacy of programmed death protein-1/ ligand-1 (PD-1/L1) inhibitors. Among the various concomitant drugs, proton-pump inhibitors (PPI) have attracted some attention but have not reached a conclusion. We conducted a meta-analysis to evaluate the impact of PPIs on the survival of cancer patients treated with PD-1/L1 inhibitors. MATERIAL/METHODS: Related databases and conferences reports were searched. Studies that reported the relationship between PPI use and clinical outcomes of PD-1/L1 inhibitors were included. Meta-analysis was conducted to obtain pooled hazard ratios (HR)s with 95% confidence interval (CI). RESULTS: Eight studies involving 4869 cancer patients were included. Meta-analysis showed that PPI use was associated with worse overall survival (OS) (HR = 1.43, 95% CI 1.32-1.56), worse progression free survival (PFS) (HR = 1.30, 95% CI 1.20-1.40), and decreased objective response (odds ratio = 0.71, 95% CI 0.58-0.87) in cancer patients receiving PD-1/L1 inhibitors. Neither cancer type nor therapy type affected the effect of concomitant PPIs on the OS and PFS. In the subgroup of studies with a population size <500, PPIs did not reduce the OS, but the PFS. Only 1 single-center study was conducted, showing that PPI use did not affect the OS and PFS. There was no evidence of publication bias among included studies. CONCLUSION: Concomitant PPI use was correlated with worse clinical outcomes in cancer patients treated by PD-1/L1 inhibitors. Further prospective clinical and experimental studies are needed to confirm the effect and mechanism of PPI in worsening the clinical outcome of PD-1/L1 inhibitors.

The effect of chemotherapy on survival in oldest old patients with nonmetastatic triple negative breast cancer: A populationbased observational study.

WHAT IS KNOWN AND OBJECTIVE: Chemotherapy is the primary pharmacotherapy of triple-negative breast cancer (TNBC). But the benefit of adjuvant chemotherapy in the oldest old TNBC patients remains controversial. Hence, we designed this population based observational study in order to assess the survival benefit of adjuvant chemotherapy in oldest old TNBC patients with early-stage disease. METHODS: TNBC patients aged 80 years and older that with stage I to III invasive disease were identified in the surveillance, epidemiology, and end results cancer database from 2010 to 2016. RESULTS AND DISCUSSION: Of 1611 patients enrolled, 1356 (84.17%) did not receive chemotherapy. Age, race, histology, grade, T stage, N stage, and radiation were found to be strong predictors of chemotherapy recipient by multivariate logistic regression analysis. Chemotherapy significantly prolonged overall survival (OS) (HR, 0.62, 95% CI: 0.49-0.79, p < 0.001), but did not significantly reduce breast cancer specific death (BCSD) (HR, 0.92, 95% CI: 0.63-1.35, p = 0.675). These results were further confirmed by propensity score matching analysis. Chemotherapy was associated with better OS in the subgroup of patients aged 80-84 years old (HR, 0.54, 95% CI: 0.40-0.74, p < 0.001), T2-4 stage disease (HR, 0.58, 95% CI: 0.44-0.76, p < 0.001), or grade 3-4 disease (HR, 0.54, 95% CI: 0.41-0.71, p < 0.001). However, chemotherapy did not reduce the cumulative incidence of BCSD in any subgroup. WHAT IS NEW AND CONCLUSION: Chemotherapy should be considered for TNBC patients aged 80-84 years old, T2-4 disease, or grade 3-4 disease.